Corticotropin releasing factor (CRF), synonymous with corticotropin releasing hormone (CRH), is a 41 amino acid peptide that coordinates the overall response of the body to stress. As an agonist of CRF receptors (e.g., CRF1 and CRF2), CRF is well known as the primary physiological secretagogue controlling hypothalamic-pituitary-adrenal (HPA) axis activity which mediates the endocrine stress response. CRF also plays a central role in the autonomic and behavioral responses to stress. Variation in physiological levels of CRF has been correlated with various disorders including depression, anxiety, and irritable bowel syndrome.
Antagonists of CRF receptors have been shown to effectively ameliorate behavioral stress responses in animal models. It is well established that systemic administration of CRF1 receptor antagonists leads to anxiolytic and antidepressant effects in rodents. Animal model evidence also shows that CRF1 antagonists can help alleviate the symptoms of drug withdrawal, stress-induced seizures, and certain inflammations. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system. Eating disorders, such as anorexia nervosa, have also been linked to elevated levels of CRF.
Though widely dispersed throughout the central nervous system, CRF receptors are also found in peripheral systems including glandular, vascular, gastrointestinal, and immune system tissues. Accordingly, CRF antagonists are believed to have potential in treating numerous disorders of the peripheral systems. Some CRF-related disorders of peripheral systems include, for example, hypertension, tachycardia, congestive heart failure, stroke, irritable bowel syndrome, post-operative ileus, and colonic hypersensitivity. Studies have indicated that CRF1 antagonists may also be useful as hair growth stimulators.
Numerous articles have reported the physiological role of CRF and the potential therapeutic activity of non-peptidic CRF receptor antagonists. Some of these articles, detailing much of the above discussion, include, for example; Gilligan, et al., J. Medicinal Chem., 2000, 43, 1641, Newport, et al., Curr. Opin. Neurobiology, 2000, 10, 211; Mastorakos, et al., Ann. N.Y. Acad. Sci., 2000, 900, 95; Koob, et al., Ann. N.Y. Acad. Sci., 2000, 909, 170; Maillot, et al., Gastroenterology, 2000, 119, 1569; Chrousos, Int. J. Obesity, 2000, 24, Suppl. 2, S50; Owens, et al., Exp. Opin. Invest. Drugs, 1999, 8, 1849; McCarthy, et al., Current Pharmaceutical Design, 1999, 5, 289; Heinrichs, et al., Baillier's Clinical Endocrinology and Metabolism, 1999, 13, 541; Arborelius, et al., Journal of Endocrinology, 1999, 160, 1; Webster, et al., Ann. N.Y. Acad. Sci., 1998, 840, 21; and Chalmers, et al., TiPS, 1996, 17, 166; De Souza, Hosp. Practice, 1988, 23, 59; WO 02/19975; and U.S. Pat. No. 5,236,901, each of which is incorporated herein by reference in its entirety.
Separate from the compounds reported herein, some pyrimidino pyrazinone-based compounds have been reported in WO 01/62758 as kinase inhibitors and WO 01/19825 for the treatment of chemokine mediated diseases.
As evidenced by the numerous publications directed to the study of CRF and its connection with various disorders, there is a current need for new ways in which to reduce the effects of abnormal levels of CRF or CRF receptors. For example, treatment methods for alleviating or reducing the physiological and/or neurological symptoms associated with elevated levels of CRF are desirable. The compounds described herein help fulfill these and other needs.